In the 1970's and early 1980's hyperthermia was shown to have substantial potential to increase the curability of human cancer because preclinical studies of the interaction between hyperthermia and x-irradiation or anticancer drugs were so compellingly positive. To date, hyperthermia may have been shown to increase radiotherapeutic control of breast cancer recurrent on the chest wall and large neck nodes from head and neck cancers, but an impact on curability (i.e. overall survival) of patients with these or other tumors has not been documented. We believe that the reasons why hyperthermia has not reached its full clinical potential are because both its biological interactions and the physics of its delivery have yet to be optimized. Both of these factors will be addressed in the work proposed in this application. The interrelated Projects in this program will attempt to improve the clinically useful biology of hyperthermia by: 1) better defining the mechanisms responsible for thermotolerance so that we can attempt to selectively inhibit thermotolerance development in malignant tissues, and, thus, make more frequent fractionation of hyperthermia rational (Dr. Calderwood, Project I); 2) exploring whole body hyperthermia (WBH) as one of a series of positive modulators of anticancer alkylating agents (AA's) + local radiation in sophisticated animal models (Dr. Teicher, Project II); and 3) continuing to develop maximally effective combinations of anticancer drugs, local radiation and hyperthermia in the clinic (Dr. Herman, Project V). The Program Project will also attempt to improve the physics of hyperthermia delivery by: 1) testing and refining the capabilities of a new Focused, Segmented Ultrasound Machine (FSUM) in the clinic (Dr. Herman, Project V); 2) developing new 3-D computer modelling capabilities to interface with FSUM (Dr. Svensson, Project III); 3) utilizing interstitial probes which can measure tissue temperatures densely as well as tissue perfusion (Dr. Bowman, Project IVa); and 4) developing simplified 3-D temperature models which can be used in real time to improve patient treatments with the FSUM (Dr. Newman, Project IVb).